Aim of this study is to compare the efficacy and safety of two different sequences of chemotherapeutic agents in order to optimize the treatment of patients with metastatic colorectal cancer progressed to a first line chemotherapy with FOLFIRI and bevacizumab. Primary endpoint will be overall survival, defined as the time elapsed from the date of randomization to the date of patient death due to any cause, or the last date the patient was known to be alive.

Strategy A: FOLFOX-4 followed, after progression, by irinotecan/cetuximab Strategy B: irinotecan/cetuximab followed, after progression, by FOLFOX-4 Patients will be randomly assigned to one of the two treatment sequences (with 1:1 ratio) using a block design randomization procedure stratified according to center.

The patient accrual period is planned for approximately 36 months. To assess OS, all pts will be followed for up to 18 months after the last patient is randomised. The maximum estimated study duration is approximately 54 months.All statistical analyses will be based on an intention-to-treat approach. CONSORT rules will be applied to describe study flow and protocol deviations.

Randomized, Phase III, Multicenter Trial Comparing Two Different Sequences of therapyFOLFOX-4 vs FOLFOX-4 Followed by Irinotecan/Cetuximab in Metastatic Colorectal Patients Treated With FOLFIRI /Bevacizumab as First Line Chemotherapy

Cetuximab/irinotecan followed, after progression, by FOLFOX-4 (Oxaliplatin, leucovorin and 5-fluorouracil)

Drug: Irinotecan/Cetuximab

CET 400 mg/m2 intravenously via infusion pump given over a 120 min time and weekly CET infusions at a maintenance dose of 250 mg/m2 given over a 60 min time.

IRI 180 mg/m2 iv infusion over 30-90 min. Cycle length is 2 weeks and it is to be repeated until disease progression.

Other Name: CPT11/Cetuximab

Active Comparator: FOLFOX 4

FOLFOX-4 (Oxaliplatin, leucovorin and 5-fluorouracil) followed, after progression, by irinotecan/cetuximab

Drug: FOLFOX-4

Day 1: OXA will be administered as a 85 mg/m2 iv infusion over 2 hours; Leucovorin as a 100 mg/m2 infusion over 2 hours, 5-FU will be given as a 400 mg/m2 bolus injection, and then as a 600 mg/m2 continuous infusion over 22 hours after the first infusion Day 2: Leucovorin 100 mg/m2 (alone), followed by 5-FU 400 mg/m2 bolus injection, and 5-FU 600 mg/m2 continuous infusion after the first infusion Cycle length is 2 weeks comprising approximately 48 hours of infusion and 12 days of rest. Cycles are to be repeated every second week for a total of either 6 (12 weeks) or 12 cycles (24 weeks).

Other Name: Oxaliplatin, 5FU, Leucovorin

Detailed Description:

Target population:

Patients with histologically confirmed metastatic colorectal cancer progressed after a first line treatment containing FOLFIRI and BEV

Inclusion criteria:

Age >18 < 75 years of age

Diagnosis of histologically proven adenocarcinoma of the colon or rectum, stage IV

Assuming a randomization ratio of 1:1, 282 deaths are required in order to achieve a power of 80% of detecting a hazard ratio of 0.72 in favour of one of the two sequences, translating in an increase of median survival time from 10 to 14 months, with a type I error of 5%, two-sided, using the Mantel-Cox version of the log-rank test. With a uniform accrual period of 3 years and a follow-up of 18 months, about 350 patients will be needed to reach the target number of events.

All statistical analyses will be based on an intention-to-treat approach. CONSORT rules will be applied to describe study flow and protocol deviations.

All OS and PFS curves will be drawn with the Kaplan-Meier method. Results will be presented as Hazard Ratio (HRs) and their 95% Confidence Interval (CIs).

On annual basis, starting from the second year, an interim analysis will be conducted. In principle, no formal stopping rule will be applied, unless otherwise suggested by the DSMC. Safety reports will be drawn on annual basis.

Eligibility

Ages Eligible for Study:

18 Years to 75 Years

Genders Eligible for Study:

Both

Accepts Healthy Volunteers:

No

Criteria

Inclusion Criteria:

Age >18 <75 years of age

Diagnosis of histologically proven adenocarcinoma of the colon or rectum, stage IV

History or presence of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates use of an investigational drug or patient at high risk from treatment complications

Other malignancies within the last 5 years (other than curatively treated basal cell carcinoma of the skin and/or in situ carcinoma of the cervix)

History of psychiatric disability judged by the investigator to be clinically significant, precluding informed consent or interfering with compliance for oral drug intake

Known grade 3 or 4 allergic reaction to any of the components of the treatment

Known drug abuse/ alcohol abuse

Contacts and Locations

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Please refer to this study by its ClinicalTrials.gov identifier: NCT01030042